Very interesting research…

Among the numerous definitions for addiction, there lies yet another to define it from a biochemical perspective. Milkman (1983) defines it as ” self-induced changes in neurotransmission that result in social problem behaviors.” This definition encompasses the psychological, biochemical and social aspects of addictive processes. It is not limited to substance abuse and can be applied to any activity characterized by compulsion, loss of control and continuation of the substance despite harm. This has helped investigators gain a better understanding of the nature of addiction.

A very interesting fact:

It has been shown that individuals turn to drugs that elicit a mood or level of arousal consistent with their mode of dealing with stress.

Those who deal with stress by confrontation choose drug stimulants.

Those who withdrawal from stress choose opiate drugs.

Others who deal with stress through activities related to imagery or fantasy turn to hallucinogens.

These differences between behavior and drug preference are thought to be biochemically driven.

The basis for biochemical activity is neurotransmission, the mechanism by which signals or impulses are sent from one nerve cell to another. The more rapid the transmission through certain central nervous system (CNS) pathways, the more intense the feeling or state of arousal. Thus,

the arousal-type person will seek activities or substances that will increase the rate of neurotransmission in the part of the brain responsible for that mood.

Those individuals that indulge in thrill-seeking behavior, such as gambling or skydiving, will choose stimulants such as amphetamines.

In contrast, those individuals who seek activities that decrease the rate of neurotransmission, such as meditation, overeating or watching excessive television, will choose depressants such as barbiturates.

Once a change in neurotransmission is brought about, whether from an activity or from a substance, the brain attempts to reestablish the rate of neurotransmission that was present before the activity or substance intake. Once the rate is reestablished, the individual becomes tolerant to the original level of the substance or activity. To achieve the desired state of arousal brought about by a change in the rate of neurotransmission the individual must increase the level of the activity. After this point, there is an altered response of the individual to the drug. Any removal of the activity or drug would then result in withdrawal symptoms. This would compensate for the altered brain chemistry and stress placed on the CNS that was established during the period of abuse.

The Mechanics of Neurotransmission

To understand the relationship between neurotransmission and addiction, one needs to have an understanding of neurotransmission itself. The Central Nervous System (CNS) is composed of the brain and spinal cord. Nerve cells or neurons connect all aspects of the nervous system. The neuron is composed of a body, axon, and dendrites. The Dendrites receive and transmitthe nerve impulse, the body integrates the signal, and the axon propagates it. The body will make the decision as to whether or not to transmit the signal or inhibit the signal from continuing on to the next neuron. The CNS is malleable, rather than hard-wired, and must be able to rapidly adapt to varying signals.

Between nerve cells there are spaces called synaptic junctions.

Figure %: Synaptic Junctions

Small molecules known as neurotransmitters are released into the synaptic junction from the pre-synaptic terminal. After they are released, the neurotransmitters can be degraded by enzymes or be integrated into the post-synaptic membrane. Once the neurotransmitters are picked up by the post-synaptic neuron in sufficient quantities, the membrane will depolarize and the signal will be transmitted.

Like a lock and key, only certain shapes and sizes of neurotransmitters will fit into the receptors of the post-synaptic neuron. In the post-synaptic terminal, there are receptors that, if bound to by neurotransmitters, will activate adenylate cyclase (). This enzyme converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (cAMP). cAMP has the effect of increasing membrane sensitivity and subsequent neurotransmission. The direction of the impulse is unipolar, and is always in the same direction.

Disruptions that increase neurotransmission (Stimulants)

There are several points at which the transmission of an electrical impulse can be disrupted. Within the pre-synaptic terminal, there are enzymes that will degrade the neurotransmitters before they are released into the synaptic junction. If degraded, these neurotransmitters will never reach the post- synaptic nerve terminal, and the impulse will cease to be transmitted. Degradation can also occur within the synaptic junction itself. Enzymes that remain in the junction can be present in over or under abundance. Hence, transmission can either be enhanced or subdued. Drugs that occupy the receptor but may or may not exhibit the same effect as the neurotransmitter can saturate receptors at the post-synaptic terminal. Lastly, the cAMP pathway can be interrupted which will result in delayed or diminished transmission of the impulse. Each of these points can be altered by exogenous drug administration.

Disruptions of the Neural Networks

Research has demonstrated that changes made to neural networks can result in abnormal and even addictive behavior. For example, in some parts of the CNS, post-synaptic receptors can be occupied by the neurotransmitter dopamine (DA). If the drug Haldol is administered, it will occupy the same receptors and not allow DA to bind. This blocking inhibits the overactive neurotransmission that is associated with schizophrenia and helps to eliminate large mood swings commonly seen amongst schizophrenia patients. Cocaine, on the other hand, prevents the degradation of the neurotransmitter in the synaptic junction. This will result in an overabundance of neurotransmitter in the junction available for binding to the post-synaptic membrane. Overly saturated receptors lead to over-active transmission of the electrical impulse and result in an increased stated of arousal.

Disruptions of the pre-synaptic terminal

Other areas where neurotransmission can be disrupted are located within the pre- synaptic terminal itself. Inside the terminal are monoamine oxidases (MOA), enzymes that degrade neurotransmitters such as dopamine and norepinephrine. In some individuals, there is too much MOA, which results in a lowered level of the neurotransmitter and a subsequent state of depression. Giving these patients MOA inhibitors will transiently resolve the depressive mood.

Disruption of the cAMP system

Disruption of the cAMP system operates in a different fashion and demonstrates the neurochemical mechanism for tolerance. In its homeostatic state, the brain attempts to counter the effects of activities that result in a change of neurotransmission. Thus, an initial increase in cAMP will be countered by a decrease in adenylate cyclase. As adenylate cyclase levels are down regulated, less cAMP is produced, neurotransmission is slowed, and a change in mood results. When this occurs, the desired state of arousal or mood can only be achieved by increased activity or substance ingestion. This phenomenon, known as tolerance, is an important component of addiction and will be discussed later. The cAMP system also achieves a link between biochemistry and withdrawal symptoms. Removal of the activity or drug results in a massive decreased production of cAMP that will lead to symptoms of withdrawal, including anxiety and lethargy.

Disruptions that decrease neurotransmission

The neurochemical mechanisms described above are important in the actions of amphetamines and other stimulating activities that increase the rates of neurotransmission and change the behavior of arousal-prone individuals. In contrast, substances or activities that decrease neurotransmission, such as barbiturates or meditation, bring about a release of endorphins or enkephalins. These naturally occurring substances act as the body’s own opiates. Opiates or enkephalins attach themselves to the pre-synaptic terminal () causing a decrease in the release of the neurotransmitter. This decrease in release of the neurotransmitter results in a slowing of neurotransmission that in turn results in the effect desired by satiation-prone individuals. The body counteracts these effects by increasing the level of adenylate cyclase, which will in turn increase the level of camp and the general level of neurotransmission. This will produce an undesirable feeling and the individual will have to increase the dose to achieve the desired effect. In time, the individual will exhibit tolerance and need to increase the satiating activity or substance to achieve the desired effect. Upon removal of the activity or substance, quantities of cAMP and the rate of neurotransmission will increase. This will result in a state of agitation for individuals withdrawing from opiate ingestion or satiation activities.

Hallucinogens

Although the mechanisms of action for stimulants and opiates are well understood, the effects of hallucinogens are not. There is some data, though, that does support a neurochemical mechanism for the behavior resulting from the use of hallucinogens. There is a very close relationship between the structure of the neurotransmitter seratonin and various hallucinogenic compounds such as LSD, psilocin and DMT. Although not fully understood, it also appears as though tolerance and withdrawal can result from abuse and addiction of these substances. For those exogenous drugs that have structural similarities to endogenous neurotransmitters, some neurochemical mechanism of action is likely to underlie the change in behavior noted with the use of the substance.

Tolerance and Physical Dependence

The consequences of drug addiction, tolerance and physical dependence, have been studied extensively at the molecular and cellular levels. Tolerance occurs as a result of prolonged exposure to a drug. Physical dependence is a physiologic and biochemical adjustment to the presence of an addicting drug.

Tolerance

There are two kinds of tolerance: metabolic and cellular. Metabolic tolerance reflects an individual’s increased ability to metabolize the drug so that the drug concentration in contact with the sites of action is reduced. Cellular tolerance represents decreased sensitivity to a given drug concentration. It is an example of biochemical regulation at the cellular level to maintain homeostasis. Cellular tolerance can be selective, that is, tolerant to only one specific drug, or can manifest cross-tolerance to unrelated drug families. A suggested mechanism for cross-tolerance is receptor desensitization that can be homologous (limited to one receptor) or heterologous (involving several receptors that converge onto a single pathway).

Physical Dependence

Physical dependence is both a physiologic and a biochemical adaptation to an addicting drug that allows the addicted individual to appear seemingly normal while under a drug concentration that produces the desired effect. By definition, physical dependence is accompanied by some degree of tolerance. The “withdrawal syndrome” is often characterized biologically by effects that are opposite to the acute pharmacological actions of the drug itself. Removal of the drug will unmask an underlying pathophysiology that is noted by odd behavior. Reestablishing an effective drug concentration relieves these abnormalities.

Like tolerance, physical dependence is a consequence, not a precursor, of drug addiction. It can, however, play a role in continuing drug use after the initial use. Even after the first drug dose, a small degree of physical dependence is established. A withdrawal syndrome, no matter how mild, will follow as the initial dose wears off. Once physical dependence is established and the withdrawal syndrome ensues, drug-seeking behavior follows predictably.

As defined by Jaffe (1980), drug addiction is “a behavioral pattern of drug use, characterized by overwhelming involvement with the use of a drug (compulsive use), the securing of its supply and a high tendency to relapse after withdrawal. In addition, it is characterized by craving, withdrawal and tolerance.” Traditionally, the concept of addiction only applied to substance abuse. In recent years, the concept of addiction is not only a biological concept that is precipitated from substance abuse, but it also considers cultural, social, and cognitive or psychological influences. Addiction is best understood as an individual’s adjustment to his or her environment that is often self-destructive. It represents a pattern of coping through habituation. Rather than being a distinct disease entity, it is thought of more as a continuum of feeling and behavior.

There are three ways that drug addiction can be recognized in an individual.

1. The addicted person exhibits a heightened need for a substance. This need then leads to habits that are aimed at acquiring the substance.
2. Upon discontinued use of the abused substance, the individual suffers intensely.
3. The hallmark of addiction is the addicted individual’s willingness to sacrifice everything, to the point of self-destruction, to take the drug.

These signs are based in the biology of addiction, and therefore can be applied more appropriately to drug addiction than to addictions of other types. However, even drug addiction is not solely based on physiology. Rather, the feeling of craving and withdrawal from a drug, an object, or a behavior engages an individual’s expectations, values, and self-image for gratification. The concept of addiction provides a powerful description of human behavior that involves compulsion and self-destruction.

There are a range of factors that influence an individual’s reaction to drugs and susceptibility to addiction. Cultural and historical variations are among the most potent. These concepts are deeply rooted in society and begin influencing individuals at a very young age. By the time of maturity, when impressions are solidified, the cultural and historical perspectives of addiction are difficult to cast off. One may question why these prejudices persist through generations. Some explanatory factors are that harboring of popular prejudices is an accepted norm, that deficiencies in research strategies are poorly acknowledged, and that the legality of various substances are unsettled. Ultimately, however, theories of addiction need to include not just the biological perspective, but also the subjective perceptions, cultural, historical and individual, that comprise the complex behavior known as addiction.

Whether genetics contribute to addiction is controversial and is a derivative of the debated topic of whether genes contribute to behavior at all. The genetic basis for states such as schizophrenia and manic-depression is currently a topic of wide investigation. The behaviors that accompany these states and others appear to be influence both by genetic and environmental factors. It is neither nature nor nurture alone, rather nature and nurture that influence behavior. Such is also considered to be the case with addictive behavior, and has been most thoroughly investigated in cases of alcohol and tobacco.

There are several methods used to study the influence of genetics on behavior. They are family studies, adoption studies, twin studies, twins-reared-apart and animal studies. Through these various kinds of genetic studies, various results have implied that genes do play a role in addiction, most specifically to alcohol and tobacco. This being the case, it is likely that all behaviors are influenced to some degree by genetics, including addiction.

Family studies have shown that the incidence of alcoholism is increased in families where one or more members of the family have been diagnosed with alcoholism. Studies have indicated that the progeny of an alcoholic mother or father have two to four times the probability of becoming alcoholic than does the general population. Although little has been done to show that smoking is influenced by genetics, it is a fact that children of smoking parents are more likely to smoke. How much of this is also an environmental issue is not clear.

Adoption studies have also drawn conclusions that alcohol addiction is genetic. Groups of males that had biological but not adoptive parents that were alcoholics were compared to a group of men that had biological and adoptive parents that were not alcoholics. The former group showed an increased incidence for alcoholism four times greater than the latter. A later study (Goodwin et al., 1974) compared the incidence of alcoholism in adopted-away sons of alcoholics with their biological brothers who had been raised by the alcoholic parents. The incidence of alcoholism was identical. The work of Goodwin (1979) also demonstrated that genetic factors are not as important in determining alcoholism in females.

Twin studies and twins-reared-apart studies are the most powerful tools for evaluating genetic affects on behavior. Unfortunately, few of these studies have been used in alcohol related research. The data that has been generated, though, does support the notion that alcohol addiction is influence by genetic factors. In comparing monozygotic (identical) and dizygotic (fraternal) twins, there are different outcomes. Although twins of either category are associated with higher incidences of alcoholism, those of the monozygotic type have an even greater rate.

Animal studies have been used extensively to evaluate the genetic contributions to alcohol and nicotine addiction. Studies by Collins (1979) showed that genetics influence preference for and initial sensitivity to the severity of withdrawal from alcohol. Further investigations have indicated that both metabolism of and central nervous system sensitivities to alcohol are influenced by genetic factors. Similar conclusions have been drawn with nicotine. Mice studies conducted by Marks et al. (1983) showed that these nervous system sensitivities probably involve different brain receptors specific for nicotine. These receptors play a role in the degree of response the individual will get from the drug.

The degree to which genetic factors play a role in addictive behavior is still unclear and remains to be further investigated. The data do suggest that with alcohol, and to a lesser extent nicotine, genetic factors influence addiction considerably. Neither is influenced solely by genetics and environmental conditions appear to be notably important. An area of research that will further define the roles will be to study the affects of environmental factors on genetically susceptible people. The biochemical approach to understanding addiction is another area where genes may contribution.

Courtesy of

SparkNotes Editors. “SparkNote on Addiction.” SparkNotes.com. SparkNotes LLC. n.d.. Web. 1 Oct. 2013.